Common Variable Immunodeficiency (CVID) and LRBA Mutation: Different Clinical Phenotypes and Effects of Hematopoietic Stem Cell Transplantation (HSCT) in Three Children

Research Article | DOI: https://doi.org/10.31579/2637-8876/044

Common Variable Immunodeficiency (CVID) and LRBA Mutation: Different Clinical Phenotypes and Effects of Hematopoietic Stem Cell Transplantation (HSCT) in Three Children

  • Mach-Tomalska Monika 1*
  • Rywczak Iwona 1
  • Karolina Bukowska-Strakova 2
  • Magdalena Rutkowska-Zapała 2
  • Agnieszka Biedroń 3
  • Aleksandra Gergont 3
  • Goździk Jolanta 4
  • Pituch-Noworolska Anna 1
  • Szaflarska Anna 1,2

1 Immunology Unit.

2 Department of Clinical Immunology.

3 Neurology Clinic.

4 Department of Transplantation University Children’s Hospital in Kraków, Wielicka 265 st, 30-663 Kraków, Poland.

*Corresponding Author: Monika Mach-Tomalska, Immunology Ward, University Children Hospital w Kraków Wielicka st 265, 30-663 Kraków, Poland

Citation: Mach-Tomalska Monika, Rywczak Iwona, Karolina Bukowska-Strakova, Magdalena Rutkowska-Zapała, Agnieszka Biedroń., et all (2023), Common Variable Immunodeficiency (CVID) and LRBA Mutation: Different Clinical Phenotypes and Effects of Hematopoietic Stem Cell Transplantation (HSCT) in Three Children, J Immunology and Inflammation Diseases Therapy. 6(1); Doi:10.31579/2637-8876/044

Copyright: © 2023, Monika Mach-Tomalska. This is an open-access article distributed under the terms of The Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 17 March 2023 | Accepted: 17 April 2023 | Published: 26 April 2023

Keywords: LRBA mutation; CVID; juvenile arthritis; chronic diarrhea; Crohn-like disease; hemolytic anemia; thrombocytopenia; tetraparesis; HSCT

Abstract

LPS responsive beige-like anchor protein (LRBA) deficiency is leading to autoimmune clinical symptoms. Within clinical symptoms of LRBA deficiency are lymphoproliferation, interstitial lung disease and organomegaly suggesting ALPS or hypogammaglobulinemia. Autoimmunity and hypogammaglobulinemia leading to infections are diagnosed as common variably immunodeficiency (CVID). The course of disease is different from mild to severe life-threatening. The early onset of chronic refractory diarrhea (VEO-IBD often precedes hypogammaglobulinemia and diagnosis of CVID. LRBA deficiency was showed in 3 our patients with final diagnosis of CVID. Two of them (siblings) demonstrated early onset diarrhea at the beginning, hypogammaglobulinemia, juvenile rheumatoid arthritis and severe nervous involvement (flaccid tetraparesis) in course of disease. The third patient was initially diagnosed as ALPS due to lymphoproliferation, splenomegaly, thrombocytopenia and hypogammaglobulinemia. Therapy included immunoglobulins in regular substitution, immunosuppression according clinical symptoms with haematopoietic stem cells transplantation (HSCT) as final treatment after diagnosis of LRBA deficiency. However, despite of immune system reconstitution, there were no complete resolving of clinical symptoms. The course of CVID with LRBA in our patients support indications for early introducing of genetic study including LRBA deficiency suggesting more adequate therapy of these patients.

Abbreviations

ASD  -  atopic skin disease

CVID  -  common variable immunodeficiency

CTLA-4 –cytotoxic T lymphocyte antigen-4

GvHD –graft versus host diseases 

GLILD -   granulomatous lymphocytic interstitial lung disease

LRBA -  LPS responsive beige-like anchor protein

HSCT -  haematopoietic stem cells transplantation

HA -     hyperalimentation

IVIG   -  intravenous immunoglobulins

JRA –juvenile rheumatoid arthritis

LIP -   Lymphocytic interstitial pneumonia

MDS –myelodysplastic syndrome

MTX   -  methotrexate

MRD   -  matched related donor

MUD   -  matched unrelated donor

6MP -    6-mercaptopurine

MMF –mycofenolate mofetile

NSAIDS -non-steroid anti pain drugs

SCIG  -  subcutaneous immunoglobulins

TPN   - total parietal nutrition

VEO-IBD – very early onset of inflammatory bowel disease

Introduction

Common variable immunodeficiency (CVID) characterises variety of clinical phenotypes from mild form consisting hypogammaglobulinemia and recurrent infections with poor response to therapy associated with low production of specific antibodies to vaccines up to serious symptoms of autoimmunity including haemolytic anaemia, thrombocytopenia, organomegaly and lymphadenopathy with severe clinical course [1]. The study of possible genetic background of CVID showed different disorders with mutation in LPS responsive beige-like anchor protein (LRBA) described first time in 2012 year as one of them in patients with severe autoimmunity in CVID. Majority of LRBA deficiency is discovered within CVID patients, however, there are patients with LRBA deficiency and typical clinical symptoms without immunodeficiency. Gen LRBA is located in 4q31.3 position with 57 exons coding LRBA cytosolic protein (2851 amino acids residues) involved in protection of CTLA-4 protein present in T lymphocytes from lysosomal degradation. LRBA is playing regulating of CTLA-4 trafficking in T regulatory lymphocytes. Patients with LRBA deficiency showed deeply reduced CTLA-4 level due to rapid degradation in lysosomes [2-5]. LRBA is widely expressed within tissue, however, immune cells need activation to show expression of LRBA protein. In patients with LRBA deficiency, the number and function of T regulatory lymphocytes (Treg), class switched B memory cells and plasmablasts are reduced. Moreover, responsible for CVID with deficiency of antibodies production may be combination of disturbed differentiation and maturation of B lymphocytes including memory B cells, low number of plasma blasts and plasmocytes. In LRBA deficiency, Treg in phenotype show, the markedly decreased expression of FOXP3, CD25, CTLA-4, what resembles aberrant and reduced function of Treg cells. Moreover, in peripheral blood, the number of circulating follicular Treg is lower than in healthy control. The autophagy defects in LRBA patients lead to perturbation of mucosal homeostasis and autophagosomal processing of intracellular bacterias within mucosal cells, what might be relate to gastrointestinal syndromes e.g. chronic diarrhea in small children, colitis and Crohn-like disease in older ones, as one of pathomechanisms [2]. The reduced autophagy process is involved in B cell differentiation and increased apoptosis described in LRBA deficiency may be a possible mechanism. The disturbances in differentiation of B cells were shown in culture of B cells from LRBA patients with anti CD40/IL-4 and CD40/IL-21 stimulation [2]. Autophagy is required for the formation and maintenance of long-lived plasma cells pool in periphery. The higher apoptosis is associated and is leading to decrease of memory B cells and plasmablasts number. These deregulations within immune system supported the role of LRBA in autophagy/apoptosis process [2,6]. The observed combination of low number of Treg, increased autoimmune clones within mature naive B cells and increased number of CD21 low B cells found in LRBA deficient patients are considered as mechanisms of dominating autoimmunity within clinical symptoms in LRBA deficiency [4-7]. 

The patients with CVID and LRBA deficiency demonstrate in clinical phenotypes, recurrent infections with prolonged course and weak response to therapy, low level of specific antibodies after vaccines and hypogammaglobulinemia. In LRBA deficiency penetration of gene is high, almost full, however, the clinical phenotypes are different with severe course and fatal outcome in part of patients. Typical clinical symptom in majority of patients, are chronic diarrhea and enteropathy resistant to aggressive therapy, including prolonged systemic steroids and immunosuppression, noted as early as first year of life. In part of patients, diarrhea, thrombocytopenia are preceding hypogammaglobulinemia and diagnosis of immune deficiency with LRBA gene mutation [1,2,8]. Within group of 7 patients with LRBA - 3 of them died at age 4, 14 and 16 years of life from the uncontrolled enteropathy, colitis and complication of immunosuppressive therapy. However, within these patients were siblings (boy and girl) diagnosed as LRBA deficiency. Boy showed severe clinical course with enteropathy, thrombocytopenia, organomegaly and recurrent infections. Girl was without any clinical symptoms during time of observation [8]. In cohort of 31 LRBA deficiency patients majority (19 patients) presented severe autoimmunity, hypogammaglobulinemia, organomegaly, respiratory infections and chronic diarrhea. Within this cohort in 7 patients autoimmunity was associated with joints, similar number of patients showed neurological symptoms. These last included 1 case of myasthenia, 2 patients with cerebral granulomas, 2 patients with atrophy of optic nerve [2]. 

The most common autoimmune symptoms are hematologic (haemolytic anaemia, thrombocytopenia, leukopenia), however, diabetes, rheumatoid arthritis, Crohn-like colitis and interstitial lung disease (LIP, GLILD) are described [1-4,8,9]. 

Therapy and HSCT

Hypogammaglobulinemia typical for CVID is corrected with immunoglobulins infused intravenously or, more frequent, subcutaneously as home therapy comfortable for patients. Substitution of immunoglobulins usually is continued from time of CVID diagnosis up to time of HSCT procedure suggested as therapy for LRBA deficiency. Concomitant infections required prolonged and wide spectral antibiotics, antimycotic therapy. More difficult are autoimmune phenomena and diseases based of these mechanisms. The basic and typical therapeutic approach is systemic use of steroids as systemic usually for long time. In haematological symptoms like haemolytic anaemia, thrombocytopenia steroids are used in high dose intravenously 3-5 consecutive days followed with lower dose administered orally. In case of steroid intolerance or severe side effects of such therapy, the classical immunosuppression is introduced. For jejunal autoimmunity (colitis, Crohn disease, Crohn- like chronic inflammation, enteropathy) cyclosporine A, anti-TNF monoclonal antibodies and classic immunosuppression e.g. azathioprine, sulfosalazine are ordered in different schedules for individualised (“patient tailored”) therapy [1]. 

As supplementary, the modified diets, vitamins, probiotics, albumins, and other preparations are used to support gain of weight and prevent the effects of malabsorption and symptoms of malnutrition. The clinical condition of patient, elimination of acute and chronic infections are important factors for prognosis of HSCT procedure effects. As routine for HSCT procedure, the first step included searching for matched family donor (related e.g. siblings) with the exclusion of carriers the genetic mutation without clinical symptoms. In majority of patients, the unrelated donor is used for HSCT due to lack of related donor. The protocols of conditioning before HSCT are different, often based on busulfan, fludarabine, ATG. After HSCT in LRBA patients the course of immune system reconstitution, possible complication as GvHD are similar to post-transplantation period in other patients treated with HSCT procedures [2,8-11].

The alternative therapy, is based on regular substitution CTLA-4-Fc fusion IgG1 immunoglobulin (abatacept) in patients with CTLA-4 and LRBA deficiency. The mechanism of this monoclonal antibody is based on replacement of CTLA-4 and restore inhibitory function of T cell activation. The effects of abatacept used of this therapy in CTLA-4 and LRBA deficiency with rheumatoid arthritis symptoms were matter of time. Abatacept therapy in a cohort of 22 patients diagnosed as LRBA deficiency, showed in 16 of them, completely controlled the chronic diarrhea, lymphoproliferation, improvement of autoimmune cytopenias as well. The most effective abatacept schedule was every or every other week administration regularly. There were no serious side effects. However, within this group 2 patient with severe course of disease were relatively resistant to abatacept therapy [4,6,12]. 

In our group of children diagnosed as CVID with autoimmunity in three of them showing severe course of disease the deficiency of LRBA was diagnosed. The clinical profile of symptoms was different, even between siblings with similar LRBA deficiency and CVID.

Case Presentation

Patient 1

A girl was born as healthy full term baby. She developed chronic diarrhea from 3rd months of life. Modifications of diet and elimination of milk protein and enzyme did not improve clinical course of diarrhea. Prolonged steroid therapy slowly resolved symptoms. In biopsy of duodenum and in endoscopy, the small granular lymphoproliferation and prolonged gastritis with ulcerations were noted. During two first years of life therapy was based on  immunosuppression, steroids, eliminating diets, TPN. These symptoms were suggesting very early onset inflammatory bowel disease (VEO-IBD), however, 20 years ago this diagnosis was not commonly used [11]. In immunological tests - antibodies typical for celiac disease were absent, immunoglobulins, number of T, B lymphocytes and NK cells were within normal value for age. In following years symptoms of Crohn-like disease and gastritis were controlled with continued therapy, however, in endoscopy inflammation with granular lymphoproliferation proved with histology were present. In 6 year of life, the episode of thrombocytopenia associated with purulent paradental and gingival inflammation was cured with high dose of immunoglobulins. Two years later exacerbations of Crohn-like disease was severe with symptoms of malabsorption and malnutrition. In therapy immunosuppression (6-MP) and budesonide were again introduced. In immunological test decreasing level of IgG with low number of B memory cells were noted. Diagnosis of CVID with autoimmunity was established followed with regular immunoglobulins substitution. The following two years showed decreasing number of B lymphocytes and NK cells, Crohn-like symptoms treated with immunosuppression modified due to leukopenia as severe side effect. Slowly remission of gastrointestinal symptoms was obtained slowly. Immunoglobulins substitution stabilised IgG level within normal value, however, number of B lymphocytes and NK cells gradually decreased. The flaccid paralysis started without infections symptoms from ptosis of right eyelid without improvement after steroid and antibiotics therapy. In next week general feeling of weakness was claimed by patients and lack of control of legs including stable standing and walking were noted. In differential diagnosis - Guillain-Barre syndrome, viral or bacterial encephalitis, demyelinating process were excluded based on cerebrospinal fluid assay and neurological diagnosis of severe axonal-sensitive polyneuropathy was suggested. Aggressive therapy with high dose steroids, high dose immunoglobulins, plasmapheresis procedures were without effect. This introduced therapy is a standard for Guillain-Barre syndrome, in this child thought as atypical due to with immunodeficiency, nor fulfilling the typical criteria. Problems with swallowing leading to pneumonias suggested bulbar involvement in paretic process and force to PEG surgery. The neoplastic lymphoproliferation was excluded base on lymph node biopsy. MRI showed enlargement of spleen and liver. In 2020 year, genetic study showed LRBA mutation. Symptoms of paralysis were without improvement despite of therapy and rehabilitation. The massive muscles atrophy and contractures progressed. After parents agreement for HSCT procedures, family study of MHC determinant showed matched sister as potential related hematopoietic stem cells donor. The HSCT procedure with MRD was performed in our patient in 13 years of age.

HSCT procedure and follow up.

Conditioning was based on TreoFluTT protocol (treosulfan, fludarabine and thioTEPA) during 7 days before transplantation. Prophylaxis of GvHD included: Cyclosporine A, MMF, alemtuzumab, steroids. Post-transplantation period was without serious infections with slow reconstitution of haematopoiesis, slow improvement of motoric function specially upper extremities, inhibition of muscles atrophy. Therapy included antibiotics, red blood cells and platelets transfusions, immunoglobulins infusions according to standard procedures after HSCT, modified and adjusted to patients symptoms. After 3 months at home, she suddenly developed symptoms of gastrointestinal massive bleeding with pain. In laboratory tests antinuclear antibodies were present. Gastroscopy was without source of bleeding in stomach. The episodes of life-threatening massive bleeding with clinical symptoms of shock were noted two times within month. Colonoscopy showed multiple regions with mucous bleeding in colon and jejunum. The life-saving therapy included red blood cells, platelets and plasma transfusions, inhibitors of proton’s pump, antibiotics, steroids. The possible effect of autoimmunity, infection with CMV and Klebsiella pneumoniae, Enterococcus faecium VRE, Candida parapsilosis before HSCT and GvHD were considered as cause of gastrointestinal bleeding. In following months improvement of motor function was noted, however, she still demonstrates paraplexis of legs. Gastric tube and central catheter were removed. Immunosuppressive therapy was stopped. The reconstitution of haematological and immune system is protecting her from infections. She is under Transplantology Outpatient follow up examined every 6 months.

Patient 2

This patient is a brother of patient 1. His history started in first year of life with chronic bleeding diarrhea, resulting underweight, malnutrition and symptoms of atopic skin disease. Therapy with steroids, modify diet was helpful but diarrhea did not resolve completely. In next year exacerbation of diarrhea, food allergy resulted with protein loosing enteropathy, malnutrition, inhibition of growth, general oedema, ascites. In therapy albumin infusions, steroids, inhibitors of protons pump, TPN with central catheter were used. The improvement was obtained, however, in next year exacerbation of diarrhea was like before despite of prolonged steroid and modify diet in therapy. Protein loosing enteropathy, oedema, malnutrition were again treated with high dose steroids. After two years of steroid therapy serious side effects were present including osteoporosis, Cushing’s symptoms in 4 years old boy. The immunological assay showed IgG level below normal value for age with IgA and IgM within normal value. Steroids were reduced and azathioprine was introduced with established diagnosis of Crohn’s disease. The following assay showed immunoglobulins level within normal value for age, proportions of lymphocytes T subpopulations, numbers of T lymphocytes, activated T lymphocytes and B lymphocytes were within normal value. Therapy with azathioprine and steroids improved clinical state of patient and in following months immunosuppression was suspended in summer. However, in late autumn the exacerbation of Crohn’s symptoms was noted with protein loosing enteropathy, diarrhea and, for the first time, swollen joints (hip, knee, ankles and elbow). The juvenile rheumatoid arthritis (JRA) was diagnosed as co-existent symptoms to Crohn’s disease. Therapy was switched to methotrexate (MTX), non-steroid anti-inflammatory drugs (NSAIDS) and low dose of steroids as therapy for JRA in patient with other chronic disease (patient-tailored therapy). In next year symptoms JRA were present without remission despite of therapy. pancreatic enzymes and modified of abdomen enlargement of lymph nodes, infiltrations of jejunum walls (“thicker”) was seen. Laboratory tests showed increase of liver enzymes level, high amount of calprotectin in stool, hypogammaglobulinemia (IgG, IgM), decrease of B cells number. From this time diagnosis of CVID was established (8 years and 4 months of age) with substitution of immunoglobulins in consequence. After LRBA mutation showed in sister, the genetic study was undertaken with results indicating present LRBA mutation. The immunosuppressive therapy (MTX, sulfasalazine, steroids) was continued, however, symptoms of JRA were persistent without remission. Severe clinical course of JRA, Crohn’s disease lead to underweight, inhibition of growth and poor general condition of patient. Moreover, the immunoglobulins used in dose 0.8-1.0 g/kg b.w. resulted in IgG level close to lower limit or even below limit for age, the number of T and B lymphocytes were below normal value. The HSCT procedure was considered and accepted, so the stem cells transplantation was undertaken for patient 9.5 years old. Conditioning included busulfan, fludarabine and campath (BuxFlu Campath) followed with transplantation of hematopoietic stem cells from matched unrelated donor (MUD). The follow-up after HSCT procedure was uneventful with supplementation of steroids (due low level of cortisol), immunoglobulins and GM-CSF. Prophylaxis of GvHD was based on cyclosporine and MMF with good toleration. He was discharged home after 34 days post HSCT with regular checking in Transplant ology Outpatient. One year and half patient claimed pain of joints (knee, ankles and fingers). The reactivation of JRA was diagnosed with cyclosporine and steroids as therapy, however, without improvement, so etanercept was introduced as second line of therapy. The examination of patient showed osteoporosis, enlargement of spleen, changes of jejunum like in food intolerance, swelling joints with pain, limitation of movement and contractions. Therapy with etanercept released joints symptoms, however, shortly after ceased the etanercept therapy left knee was painful and swollen again. Currently, patient is on continued etanercept therapy, steroids due to secondary hypocortisolaemia, antibiotics and antiviral prophylaxis. He is under multi-specialists care – rheumatology, endocrinology, transplantology, immunology and gastrology.

Patient 3

The leukopenia and thrombocytopenia with haemorrhagic diathesis at age 3 years 8 months treated with steroids and immunoglobulins intravenously with good response was the first symptom of disease. In laboratory fresh infection with common viruses were excluded, immunoglobulins were within normal value for age. The next episode of thrombocytopenia was 4 months later. In laboratory tests immunoglobulins were within normal value, bone marrow aspiration showed normal haematopoiesis without lympho- or myelo-proliferation. In assay of lymphocytes in peripheral blood small number of double negative T cells were noted. Together with autoimmunity, enlargement of lymph nodes, spleen and liver the clinical initial diagnosis of ALPS was suggested. The results of laboratory tests showed normal expression of Fas and FasL, low percentage of double negative TCR α/β T cells, what did not support this diagnosis. In this time HRCT of lungs showed changes indicating possibility of LIP/GLILD. Therapy with steroids and MMF was effective and lungs infiltrations resolved (13). The next episode of thrombocytopenia and haemolytic anaemia were half of year later treated successfully with steroids, immunoglobulins and MMF. The laboratory tests showed hypogammaglobulinemia. Based on this, the diagnosis of common variable immunodeficiency (CVID) with autoimmunity was suggested with regular substitution of immunoglobulins beginning with intravenous form followed with subcutaneous form. In next year, despite of regular substitution of immunoglobulins (0.5-0.7g/kg b.w.) episodes of thrombocytopenia were noted, in clinical features enlargement of spleen was present. In therapy MMF was changed to rapamycine. In 5 years old patient, the results of genetic study showed LRBA mutation followed with consideration of HSCT as curative procedure. Up to the time of HSCT procedure with unrelated donor (MUD), patient was treated with sirolimus, steroids (in episodes of thrombocytopenia exacerbations) and regular immunoglobulins infusions. In USG of abdomen enlargement of spleen (megaspleen), liver, lymph nodes were persistently present. Two months before planned HSCT procedure patient showed severe diarrhea without detectable pathogen (viral, bacterial or mycotic) in stool. Basic therapy (steroids, MMF (instead of rapamycine), immunoglobulins) was continued with mesalazine, hepatoprotection, albumin, pancreatic enzymes and modified diet due to diarrhea. Within month diarrhea slowly improved but did not resolve completely. Patient was transferred to HSCT procedure with central catheter, splenomegaly, lymphadenopathy, chronic diarrhea, dispersed small infiltrations (“regions of consolidations”) in lungs. In laboratory tests the blood parameters, immunoglobulins level, lymphocytes subpopulations and numbers, liver, thyroid and thrombotic parameters were within normal value. The conditioning before HSCT was based on Treo Flu TT schedule followed with unrelated donor’s bone marrow transplantation. The reconstitution of neutrophils, platelets (>20000/ul) was noted between 23 to 26 days after HSCT with Cyclosporine A and steroids as GvHD prophylaxis. The next serious problem was the reactivation of EBV infection. To prevent possible induction of lymphoproliferation of infected B cells, rituximab was added into therapy for the elimination of B lymphocytes. EBV infection was under control, however, hypogammaglobulinemia was most serious side effect of rituximab therapy. In this period of therapy infusion of immunoglobulins were sporadic according clinical symptoms. However, following assay showed low level of immunoglobulins without tendency to increase and normalisation, what indicated requirement for regular substitution of immunoglobulin. Now, patient is in good condition without symptoms of disease, on regular substitution of immunoglobulins. The patient is under Transplantation Outpatient for follow up. 

DataPatients 1   R.A.Patient 2     R.M.Patients 3 K.O.
Age of onset3 months3 months3 years 8 months
CVID diagnosis8 years7 years4 years 7 months
Genetic study13 years9 years5 years
Gendergirlboyboy
Clinical diagnosisGastritis, Crohn-like disease,ASD, Crohn disease protein loosing enteropathy, malnutrition, JRA 

ALPS (excluded),

Autoimmune thrombocytopenia,

haemolysis, LIP, 

Clinical symptoms

Chronic diarrhea with blood in stool, thrombocytopenia, malabsorption, enteropathy,

flaccid tetraparesis,

Chronic diarrhea, malnutrition, enteropathy, multi joints inflammation, osteoporosis,

Recurrent episodes of thrombocytopenia, splenomegaly, cytopenia, lymphocytic pneumonia, general lymphadenopathy,

chronic diarrhea

Endoscopy/biopsyIn gastric and colon: infiltrations with neutrophils, duodenum: diffused fine lymphogranular proliferation, Marsh 3c villous depletion Joint fluid: lymphocytic infiltration, high level of cytokines, Jejunum: infiltrations and inflammationLymph node and lung: infiltrations with lymphocytes mainly T cells – exclusion of lymphoproliferation (HD, NHL), TBC infection, diagnosis of LIP 
Therapy Steroids systemic (high dose), budesonid, azathioprine, 6MP, antimycotic, antibiotics, TPN,  HA (PEG), IVIG, plasmapheresis  (central catheter), Steroids systemic, 6MP, MTX, NSAPD, sulfasalazine,  TPN, antibiotics (periodically)

Steroids systemic, IVIG (high doses), 

antibiotic, antimycotics, MMF, (central catheter)

Immunoglobulin substitution

Since CVID diagnosis

0.4-0.8g/kg b.w. IVIG/SCIG, 1.0-2.0g/kg b.w. IVIG in tetraparesis

0.4-0.8g/kg b.w. as regular, during Crohn disease and JRA – 1.0 g/kg b.w.Regular for CVID – 0.4-0.6g/kg b.w.,1.0-2.0g/kg b.w. for AIH and thrombocytopenia
Final therapyHSCT from MRD HSCT from MUDHSCT from MUD
OutcomeReconstitution of immune system, paraparesis (legs) with slow improvement, Reconstitution of immune system, reactivation of JRA symptoms (therapy – anti-TNF, CsA, steroids)Reconstitution of immune and haematological system, reactivation of EBV infection (rituximab therapy), secondary hypogammaglobulinemia, regular   substitution of immunoglobulins
Time of follow up2 years 2 months2 years 1 month2 years 11 months

Table 1: Patients characteristics

Family memberGenetic resultsComments 
Mother      R.B.c.2449C>T, g.145203 C>TPathogenica
Father      R.Sz.c.7404_7405delGA, g.694378_694379delGAPathogenica
Patient 1 R.A.

c.2449C>T; p.Gln817,  c.7404_7405delGA, 

p.Asp2502GInfsTer40

Heterozygotic

Pathogenic

c
Patient 2 R.M.

NM_006726.4 c.[2449C>T] [7504_7505delGA]

NP._006717.2 p. [Gln817 Ter] [p.Asp2502GInfsTer40]

CVID8

OMIM#614700

b
Sister 1     R.K.LRBA exons 20 and 51 without changesNo pathogenic variantsa
Sister 2     R.K.

c.7504_7505delGA, g.694378_694379delGA

p.Asp2502GInsfTer40

pathogenica
Brother 1 R.Ł.cDNA.7748_7749delGA, g.694378_694379delGAPathogenica
Patient 3 K.O.Variant: c.2836_2839 del.Pathogenicc

Table 2: Genetic study LRBA in family of patient 1 and 2 (siblings) and patient 3

Laboratory:

      a.-Diagnostic Laboratory, Department of Clinical Immunology,

       University Children Hospital in Kraków

      b.-Medical Pediatric Laboratory, Laboratory of Immunopathology and Genetics Clinical Department of Pediatry, Oncology and Hematology in Łódź

      c.-Warszawa ?

Data

Patient 1

before    in course

IVIG/SCIG

Patient 2

before    in course

IVIG/SCIG

Patient 3

before  in course

IVIG/SCIG

Immunoglobulin 

IgG – g/l   (L-low)

IgA – g/l

IgM – g/l

IgE  -  (IU/ml)

 

5.49,(L)      8.61,   

1.09,           0.74,

0.67,           0.39

119.0         23.0

 

4.52,(L)    4.53,(L)*

1.12,         0.64,(L)

0.27,(L)    0.19,(L)   

 

4.71(L)         8.92

0.32              0.40

0.32 (L)        0.72

T lymphocytes: total/ul

    CD3     (/ul)

    CD4    (/ul)

    CD8     (/ul)

CD3/HLA-DR  (/ul)

TCRa/b TCRg/d (%)(%)

T reg  (%)

2020         1390

1279         1243

 853           838

 426           349

 264

61,  2

 

                 1096 (L)

                   753

                   355

                   343

                   102

 819 (L)     1459

 721           1226

 508             788

 156             336

 180 (H)

94.2, 2.5   

  7.1              9.6

B lymphocytes:     

CD19       (/ul) 

B memory cells:

Class switch    (/ul)

 

 345          56 (L)

 

  23 (L)

 

                    55 (L)

 

   16 (L)    102 (L)

 

     5 (L)      24 (L)

NK cells:      (/ul) 386          84 (L)                    288   82 (L)    102 (L) 

Other important data:

ASCA IgA U/l, IgG U/l

ANA (screening)

 

                     23.2

negative

 

Negative

negative

 

 

negative

Complement level: 

 C3c g/l

 C4   g/l 

 

1.16,

0.21

 

1.35

0.24

 

  1.21        1.24

  0.07        0.05

Adhesive moleculeNDNDpresent
Fas, FasL expressionNDNDnormal
T cells double negativeNDNDwithin normal range

*enteropathy, IVIG – 1.0g/kg b.w.

L – value below normal

H – value above normal

Table 3: Immunological laboratory data

Discussion

Presented siblings showed similar symptoms of chronic, severe, therapy refractory diarrhea as first signal of gastrointestinal involvement based on autoimmunity. Hypogammaglobulinemia occurred later, suggesting diagnosis of CVID with autoimmunity. Both patients were diagnosed as LRBA deficiency, however, the clinical profile was different with severe JRA in boy and neurological involvement demonstrated as flaccid tetraparesis in girl. The genetic results of LRBA gene showed different variants with heterozygotic pathogenic mutation in girl and homozygotic pathogenic mutation in boy. The other family members showed variations registered as pathogenic without development of clinical symptoms of disease. The severity of clinical course with secondary symptoms supported decision of HSCT as curative procedure. Differences between siblings in clinical course are visible after HSCT – reactivation of JRA in boy, slow resolving of flaccid paralyse symptoms without new events in girl. Our patient 3 was initially diagnosed as ALPS due to suggestive clinical symptoms - lymphoproliferation, spleen enlargement and autoimmunity. According to this initial clinical diagnosis patients was treated with rapamycine as typical apoptosis-inducing therapy in ALPS. The results of laboratory tests (expression of Fas, FasL and double negative T lymphocytes TCR a/b) did not fulfilled criteria of ALPS, so diagnosis of ALPS was excluded. The overlapping of ALPS symptoms and CVID autoimmune symptoms were suggested indicating requirement for detailed and precise differential diagnosis to identify ALPS patients due to apoptosis-inducive therapy with rapamycin (14,15). Nowadays, the clinical symptoms suggesting ALPS but with monogenic background is defined as ALPS-like syndrome for differentiation from classic, typical ALPS, based on apoptosis disorders. ALPS-like syndrome is associated with other immune disorders diseases as additional combination of clinical symptoms often improved with rapamycin therapy (5,6). 

LRBA deficiency– clinical problems – JRA, neurological symptoms

Prevalence of JRA in children with diagnosis of CVID is about 10-15

Conclusions

The genetic study of CVID cases with severe course affecting multiple organs (early onset diarrhea, autoimmune disorders, lymphoproliferation) should include CTLA-4/LRBA genes mutations.

HSCT procedure is indicated as curative therapy, however, risk of persistence some of disease symptoms should be considered.

References

Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.

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Virginia E. Koenig

Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.

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Delcio G Silva Junior

Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.

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Ziemlé Clément Méda

Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.

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Mina Sherif Soliman Georgy

We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

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Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

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Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

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Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

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Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

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Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

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Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

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Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

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Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad

Clinical Cardiology and Cardiovascular Interventions, we deeply appreciate the interest shown in our work and its publication. It has been a true pleasure to collaborate with you. The peer review process, as well as the support provided by the editorial office, have been exceptional, and the quality of the journal is very high, which was a determining factor in our decision to publish with you.

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Gomez Barriga Maria Dolores

The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews journal clinically in the future time.

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Lin Shaw Chin

Clinical Cardiology and Cardiovascular Interventions, I would like to express my sincerest gratitude for the trust placed in our team for the publication in your journal. It has been a true pleasure to collaborate with you on this project. I am pleased to inform you that both the peer review process and the attention from the editorial coordination have been excellent. Your team has worked with dedication and professionalism to ensure that your publication meets the highest standards of quality. We are confident that this collaboration will result in mutual success, and we are eager to see the fruits of this shared effort.

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Maria Dolores Gomez Barriga

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, I hope this message finds you well. I want to express my utmost gratitude for your excellent work and for the dedication and speed in the publication process of my article titled "Navigating Innovation: Qualitative Insights on Using Technology for Health Education in Acute Coronary Syndrome Patients." I am very satisfied with the peer review process, the support from the editorial office, and the quality of the journal. I hope we can maintain our scientific relationship in the long term.

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Dr Maria Dolores Gomez Barriga

Dear Monica Gissare, - Editorial Coordinator of Nutrition and Food Processing. ¨My testimony with you is truly professional, with a positive response regarding the follow-up of the article and its review, you took into account my qualities and the importance of the topic¨.

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Dr Maria Regina Penchyna Nieto

Dear Dr. Jessica Magne, Editorial Coordinator 0f Clinical Cardiology and Cardiovascular Interventions, The review process for the article “The Handling of Anti-aggregants and Anticoagulants in the Oncologic Heart Patient Submitted to Surgery” was extremely rigorous and detailed. From the initial submission to the final acceptance, the editorial team at the “Journal of Clinical Cardiology and Cardiovascular Interventions” demonstrated a high level of professionalism and dedication. The reviewers provided constructive and detailed feedback, which was essential for improving the quality of our work. Communication was always clear and efficient, ensuring that all our questions were promptly addressed. The quality of the “Journal of Clinical Cardiology and Cardiovascular Interventions” is undeniable. It is a peer-reviewed, open-access publication dedicated exclusively to disseminating high-quality research in the field of clinical cardiology and cardiovascular interventions. The journal's impact factor is currently under evaluation, and it is indexed in reputable databases, which further reinforces its credibility and relevance in the scientific field. I highly recommend this journal to researchers looking for a reputable platform to publish their studies.

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Dr Marcelo Flavio Gomes Jardim Filho

Dear Editorial Coordinator of the Journal of Nutrition and Food Processing! "I would like to thank the Journal of Nutrition and Food Processing for including and publishing my article. The peer review process was very quick, movement and precise. The Editorial Board has done an extremely conscientious job with much help, valuable comments and advices. I find the journal very valuable from a professional point of view, thank you very much for allowing me to be part of it and I would like to participate in the future!”

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Zsuzsanna Bene

Dealing with The Journal of Neurology and Neurological Surgery was very smooth and comprehensive. The office staff took time to address my needs and the response from editors and the office was prompt and fair. I certainly hope to publish with this journal again.Their professionalism is apparent and more than satisfactory. Susan Weiner

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Dr Susan Weiner

My Testimonial Covering as fellowing: Lin-Show Chin. The peer reviewers process is quick and effective, the supports from editorial office is excellent, the quality of journal is high. I would like to collabroate with Internatioanl journal of Clinical Case Reports and Reviews.

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Lin-Show Chin

My experience publishing in Psychology and Mental Health Care was exceptional. The peer review process was rigorous and constructive, with reviewers providing valuable insights that helped enhance the quality of our work. The editorial team was highly supportive and responsive, making the submission process smooth and efficient. The journal's commitment to high standards and academic rigor makes it a respected platform for quality research. I am grateful for the opportunity to publish in such a reputable journal.

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Sonila Qirko

My experience publishing in International Journal of Clinical Case Reports and Reviews was exceptional. I Come forth to Provide a Testimonial Covering the Peer Review Process and the editorial office for the Professional and Impartial Evaluation of the Manuscript.

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Luiz Sellmann